Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France.
Assistance Publique - Hôpitaux de Paris, Département de Virologie, GHU Paris-Est, Paris, France.
Gut. 2021 Dec;70(12):2373-2382. doi: 10.1136/gutjnl-2021-324554. Epub 2021 Sep 17.
Regulation of alternative splicing is one of the most efficient mechanisms to enlarge the proteomic diversity in eukaryotic organisms. Many viruses hijack the splicing machinery following infection to accomplish their replication cycle. Regarding the HBV, numerous reports have described alternative splicing events of the long viral transcript (pregenomic RNA), which also acts as a template for viral genome replication. Alternative splicing of HBV pregenomic RNAs allows the synthesis of at least 20 spliced variants. In addition, almost all these spliced forms give rise to defective particles, detected in the blood of infected patients. HBV-spliced RNAs have long been unconsidered, probably due to their uneasy detection in comparison to unspliced forms as well as for their dispensable role during viral replication. However, recent data highlighted the relevance of these HBV-spliced variants through (1) the trans-regulation of the alternative splicing of viral transcripts along the course of liver disease; (2) the ability to generate defective particle formation, putative biomarker of the liver disease progression; (3) modulation of viral replication; and (4) their intrinsic propensity to encode for novel viral proteins involved in liver pathogenesis and immune response. Altogether, tricky regulation of HBV alternative splicing may contribute to modulate multiple viral and cellular processes all along the course of HBV-related liver disease.
可变剪接调控是真核生物扩大蛋白质组多样性的最有效机制之一。许多病毒在感染后会劫持剪接机制来完成其复制周期。对于乙型肝炎病毒（HBV），已有大量报道描述了长病毒转录本（前基因组 RNA）的可变剪接事件，该转录本也可作为病毒基因组复制的模板。HBV 前基因组 RNA 的可变剪接允许合成至少 20 种剪接变体。此外，几乎所有这些剪接形式都会产生缺陷颗粒，在感染患者的血液中检测到。HBV 剪接 RNA 长期以来一直未被重视，可能是由于与未剪接形式相比，其检测难度较大，以及在病毒复制过程中作用不大。然而，最近的数据通过以下方式强调了这些 HBV 剪接变体的相关性：（1）在肝脏疾病过程中对病毒转录物的可变剪接进行反式调控；（2）形成缺陷颗粒的能力，这是肝脏疾病进展的潜在生物标志物；（3）调节病毒复制；以及（4）它们内在倾向于编码参与肝脏发病机制和免疫反应的新型病毒蛋白。总之，HBV 可变剪接的复杂调控可能有助于调节 HBV 相关肝脏疾病过程中的多种病毒和细胞过程。
